1. Field of the Invention
The present invention is directed to the prevention and treatment of an allergic disorder. In particular, the invention relates to the administration of polypeptides of the unique domain of the tyrosine kinase, Lyn, to the cells of a subject having, or at risk of having, an allergic disorder. The polypeptides act within the cells to bind the cytoplasmic domain of the high affinity receptor of IgE (Fc.epsilon.RI) and inhibit signaling through the receptor which would result in release of histamines and other substances associated with an allergic reaction, thereby preventing or treating an allergic disorder.
2. Background Art
The family of proteins known as the "multichain immune recognition receptors" includes the antigen receptors on B and T-lymphocytes and Fc receptors including the receptor with high affinity for IgE (Fc.epsilon.RI) (1). Highly homologous in structure, all these receptors utilize, at least in part, a common mechanism to initiate cellular responses: multi-valent interactions with antigen leads to aggregation of the receptors and is followed by enhanced phosphorylation of tyrosines, in the Immune-Receptor Tyrosine-based Activation Motifs (ITAMs) within the cytoplasmic domains of the receptor itself, by a receptor-associated Src-family kinase (2).
Aggregation of the Fc.epsilon.RI on mast cells initiates a cascade of events leading to degranulation and release of mediators responsible for the symptoms of atopy. Among the earliest events in the Fc.epsilon.RI cascade is the phosphorylation of tyrosines in the ITAMs on the .beta. and .gamma. chains of the receptor by the Src-family kinase, Lyn.
Several groups have studied the interaction between Fc.epsilon.RI and Lyn kinase by a variety of techniques and have demonstrated (7-10) a direct interaction between the kinase and the C-terminal cytoplasmic extension of the receptor's .beta. chain. Previous studies have also demonstrated that two forms of Lyn, designated Lyn A and Lyn B, are produced by differential mRNA splicing, both of which behave equivalently (5) and become equivalently attached to the receptor after chemical cross-linking (4).
For Fc.epsilon.RI, a "transphosphorylation" mechanism has been demonstrated that accounts for the earliest cascade events (3,4). Data from these earlier studies showed that a small percentage of resting (unphosphorylated) receptors are constitutively associated with Lyn and this constitutive association with the kinase is an absolute requirement for the initial phosphorylation of the receptor.
The present invention provides polypeptides comprising the unique region of the Lyn kinase which bind the C-terminal cytoplasmic domain of the .beta. chain of the Fc.epsilon.RI and inhibit activation of the Fc.epsilon.RI-mediated cascade of events that induce an allergic response and methods for the use of these polypeptides in treating or preventing allergic disorders.